2. Material and Methods
4.9 Concluding remarks
The role of immunoproteasome expression in the brain, and its involvement in neurodegenerative diseases first start to be realized.
In this study we could show that upon LCMV infection an accumulation of immunoproteasomal precursor complexes can be observed in the brain of intracranially infected mice. Concerning the expression of immunoproteasomal subunits in microglia as well as in astrocytes, we do not know till now, if this
Immunoproteasome assembly in the brain of LCMV-infected mice Discussion
immonoproteasome exclusively represents mature or immature immunoproteasome.
Our isolation experiments of CD11b+ cells strongly indicate that the expressed immunoproteasome in microglia represents mature immunoproteasome. However, it also seems possible that, following the long isolation procedure, additional precursor complexes are rapidly degraded due to their relative instability and thereby can not be detected in the subsequent western blot analysis.
A possible option to assess this question maybe a histological approach by perfoming a co-staining of immunoproteasomal subunits (MECL-1 or LMP2), Iba-1 as a marker for microglia, and UMP1 as a marker for immature precursor complexes.
UMP1 is degraded upon the final maturation step by the proteasome itself and is exclusively associated with pre-mature porteasome complexes underlining its potential role as a marker of immature proteasome-complexes. Unfortunately, no good antibodies against UMP1 are available to date and the assumption that UMP1 is buried inside the proteasome to coordinate ß-subunit assembly (Ramos et al. 1998)(Witt et al. 2000) further could complicate the situation.
Another possibility that may help to solve this problem would be an in vitro model, where - in analogy to our in vitro studies with astrocytes - a microglia cell line, like BV-2 is stimulated with IFN-γ, and the maturation status of immunoproteasomal subunits further is analysed by western blot.
Concerning the question, in which cells the immunoproteasomal precursors accumulate in vivo following intracranial LCMV-infection, our in vitro data strongly suggest astrocytes as candidates for this accumulation.
Taken into account the simultaneous, but strongly reduced generation of mature immunoproteasome in the brain, it is justified to challenge the relevance of such a precursor accumulation in the presence of mature immunoproteasomes. However, based on our data that propose a cell-type specific accumulation of immunoproteasomal precursors in astrocytes, it is conceivable that the reduced cytosolic expression of mature immunoproteasome and/or a potential absence of homogenous immunoproteasomes indeed is relevant considering the versatile functions of these cells during the inflammatory response.
Immunoproteasome assembly in the brain of LCMV-infected mice Discussion
Understanding the role of immunoproteasome expression as well as the role of its reduced formation in the brain could provide new insights into how an immune response is regulated in an immuneprivileged organ, and how active immune tolerance can be attained. Immunoproteasome-specific inhibitors like PR-957 will help to elucidate these questions and may represent a promising strategy for the treatment of chronic inflammation–associated, neurological disorders.
Immunoproteasome assembly in the brain of LCMV-infected mice
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